CD47
CD47 (dalla terminologia genetica in inglese: C'luster of '''D'ifferentiation 47) oppure (dalla terminologia delle proteine di membrana '''integrin associated protein IAP) é una proteina transmembranaria che negli umani è codificata dal gene CD47. La CD47 appartiene alla superfamiglia delle immunoglobuline e si lega con le proteine integrine di membrana e inoltre lega il ligando thrombospondina-1 (TSP-1) e una proteina regolatoria di segnale alfa ( SIRPα). Questo è perché la proteina IAP prodotta dal gene CD-47 agisce come un segnale don't eat me (non mi mangiare) per il sistema immunitario e conduce alla fibrosi dell'organo interessato.https://medicalxpress.com/news/2017-04-fibrosis-reversed-dont-blocked-stanford.html |}} Proteina multifunzionale Il gene CD47 è coinvolto in una serie di processi cellular processesi, includendo l'apoptosi, proliferazione, l'adesione, e la [migrazione. Inoltre ha un ruolo chiave nalla risposta immune e nell'[angiogenesi. CD47 è espressa in quasi tutte le cellule umane e si è visto che è sovra-espressa in molte diverse cellule tumorali. Struttura La proteina espressa dal CD47 è un recettore di membrana pesante 50 kiloDalton che ha un domain N-terminal che sporge al di fuori della cellula, con un IgV domain, cinque domain transmembranari, e una corta coda C-terminale intracellulare. Esistono quattro varianti isoformi (per via dello splicing alternativo del CD47 che differiscono soltanto nella lunghezza della coda citoplasmatica. Isoforme del CD47 La Forma 2 è la forma più ampiamente espressa che si trova in tutte le cellule del circolo ematico e in qualle immunitarie. La seconda isoforma più abondante è la forma 4, che è predominantemente espressa nel cervello e nel sistema nervoso periferico. Soltanto i cheratinociti esprimono la forma 1. Si conosce poco sul significato funzionale di questo "alternative splicing". Nonostante, queste isoforme sono ampiamente conservate nell'evoluzione, ad esempio tra umano e topo, suggerendo un importante ruolo per i domain citoplasmatici nel funzionamento di CD47. Interazioni Thrombospondin (TSP) CD47 è un recettore ad alta affinità per la trombospondina-1 (TSP-1), una glicoproteina secreta che giuova un ruolo nello sviluppo vascolare e nell'angiogenesi, ed in questa seconda capacità l'interazione TSP1-CD47 inhibisce il segnale dell' ossido nitrico (NO2) a molteplici livelli nelle cellule vascolari. Il legame della TSP-1 al CD47 agisce su diverse funzioni cellulari fondamentali includendo la migrazione cellulare e l'adesione, la proliferazione cellulare o l'apoptosi, e giuoca un ruolo chiave nella regolazione dell'angiogenesi e infiammazione. Proteina di Regolazione del Segnale (SIRP) Il gene del CD47 interagisce con la SIRPα, un recettore inibitorio transmembranario presente sulle cellule mieloidi. L'interazione CD47/SIRPα porta alla segnalazione bidirezionale, risultando in diverse risposte "cell-to-cell" includendo l'inibizione della fagocitosi, la stimolazione della fusione tra cellule, e la attivazione delle cellule-T. Integrine Il gene CD47 interagisce con diverse integrine di membrana, più comunemente la integrina avb3. Queste interazioni risultano in complessi CD47/integrin che interessano una varietà di funzioni cellulari, includendo l'adesione, la diffusione e la migrazione. Funzione Cellule tumorali A causa dell'espressione ubiquitaria del CD47, i tipi di segnali differiscono secondo il tipo cellulare. Sembra probabile che i partner-biochimici intracellulare e associati-alle-membrane siano cruciali nek determinare la risposta cellulare delle segnalazioni CD47. Proliferazione cellulare Il ruolo dello CD47 nel promuovere la proliferazione cellulare è fortemente dipendente dal tipo cellulare e sia l'attivazione che la perdita del CD47 può dare luogo ad una proliferazione. L'attivazione del CD47 da parte del TSP-1 incrementa la proliferazione delle linee cellulari di astrocitoma umano U87 e U373 ma non dei normali astrociti. Anticorpi che bloccano CD47: terapia per il cancro? Inoltre, gli anticorpi che bloccano il CD47 inibiscono la proliferazione di cellule di astrocitoma non stimolate, ma non i normali astrociti. Anche se il meccanismo esatto non è ben chiaro, è probabile che il CD47 promuova la proliferazione grazie alla via metabolica "PI3K/Akt pathway nelle cellule cancerose ma non nelle cellule normali. Perdita del CD47: proliferazione sostenuta! La perdita del CD47 esita nella proliferazione sostenuta di cellule endoteliali murine primarie e permette a queste cellule di riprogrammarsi spontaneamente per formare cellule di tipo embrionario multipotenti in "clusters". L'espressione di alcuni "marker" delle cellule staminali, includendo c-Myc, è piuttosto elevata nelle cellule endoteliali "CD47-null" e in una linea di linfociti T che sono carenti di CD47. L'attivazione del CD47 con TSP-1 in cellule di tipo "selvaggio" inibisce la proliferazione e riduce l'espressione dei fattori di trascrizione delle cellule staminali. Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD. "Thrombospondin-1 Signaling through CD47 Inhibits Self-renewal by Regulating c-Myc and Other Stem Cell Transcription Factors". Science Report, Vol.3 (pages 1673), April 2013. doi = 10.1038/srep01673 Morte cellulare Il legame chimico della CD47 porta alla morte cellulare in molte linee cellulari normali e tumorali sia col meccanismo dell'apoptosi o per autofagia. The activation of CD47 induces rapid apoptosis of T cells. Jurkat cells and peripheral blood mononuclear cells (PBMC) incubated with the monoclonal antibody Ad22 results in apoptosis within 3 hours. However, apoptosis was not observed following culture with other anti-CD47 antibodies. The apoptosis inducing function of CD47 appears to be dependent on activation of specific epitopes on the extracellular domain. Similarly, CD47 ligation rapidly induces apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells. Treatment with a disulfide-linked antibody dimer induces apoptosis of CD47-positive primary B-CLL and leukemic cells (MOLT-4 and JOK-1). In addition, administration of the antibody prolonged survival of SCID mice implanted with JOK-1 cells. Apoptosis induction appears to be regulated by the hypoxia inducible factor 1α (HIF-1α) pathway. The RAS-transformed cell lines MDFB6 and B6ras show near complete loss of TSP-1 expression. Activation of CD47 with TSP-1 results in loss of viability in these RAS-expressing cells. Affected cells do not exhibit hallmarks of apoptosis but rather autophagy as seen by staining with acridine orange and immunoreactivity for LC3. Migration Cell migration appears to be universally stimulated by CD47 ligation and activation. The role of CD47 in cell migration was first demonstrated for neutrophils, where CD47 blocking antibodies inhibited transmigration of neutrophils and monocytes through the endothelium. These effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane. Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanoma, prostate cancer and ovarian cancer-derived cells. In a mouse model of multiple myeloma, tumor metastasis to bone was decreased in CD47-deficient mice compared with wild type controls. In mice xenografted with human non-Hodgkin lymphoma (NHL) cells, blocking CD47 function with shRNA or antibodies led to a dramatic reduction in metastasis to major organs. Stromal cells Angiogenesis Loss of CD47 promotes proliferation and increases asymmetric division of primary murine endothelial cells. Additionally, activation of CD47 with TSP-1 in wild-type primary mouse cerebral endothelial cells induces cytotoxicity, which is significantly decreased in cerebral endothelial cells derived from CD47 knockout mice. CD47 signaling may suppress angiogenesis as TSP-1 activation significantly inhibited endothelial cell migration and tube formation in vitro. In vivo, injections of TSP-1 in mice after hindlimb ischemia induces a significant decrease of blood flow recovery. The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells. CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis. Inflammatory response Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 knockout mice show reduced recruitment of blood T cells as well as neutrophils and monocytes in areas of inflammation. CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Red blood cells that lack CD47 are rapidly cleared from the bloodstream by macrophages, a process that is mediated by interaction with SIRPα. Mouse hematopoietic stem cells (HSCs) and progenitors transiently upregulate CD47 during their migratory phase, which reduces macrophage engulfment in vivo. Tumor cells can also evade macrophage phagocytosis through the expression of CD47. CD47 is highly expressed in bladder tumor initiating cells (T-ICs) compared with the rest of the tumor. Blockade of CD47 with a monoclonal antibody results in macrophage engulfment of bladder cancer cells in vitro. CD47 is also upregulated in mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line allows these cells to evade phagocytosis. Clinical significance CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s. Since then, CD47 has been found to be expressed on multiple human tumor types including acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, and other solid tumors. CD47 is also highly expressed on pediatric and adult brain tumors. High levels of CD47 allows cancer cells to avoid phagocytosis despite having a higher level of calreticulin - the dominant pro-phagocytic signal. This is due to engage of the SIRP-α of macrophage by CD47. Engagement of SIRP-α leads to inhibition of phagocytosis. Thus blocking CD47 with antibody turns off “don’t eat me” signal and favors phagocytosis. As a potential drug target Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages can initiate an antitumor T-cell immune response. Noteworthy, anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer, but also fosters the activation of cancer-specific lymphocytes: cancer cells now display mutant proteins to which the immune system can react. Humanized anti-CD47 antibody is being evaluated for the treatment of various cancers, particularly childhood brain tumors. See also * Cluster of differentiation References Further reading * Oldenborg,P.A. (2013). CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN hematology, 2013: 614619. doi: 10.1155/2013/614619 * Soto Pantoja,D.R., Kaur,S., Miller,T.W., et al. & Roberts, D. D. (2013) Leukocyte surface antigen CD47. UCSD Molecule Pages, 2(1), 19-36. * Oldenborg PA. Role of CD47 in erythroid cells and in autoimmunity. (Journal Leuk. Lymphoma vol.45, issue 7 (pag. 1319–27) 2004.doi= 10.1080/1042819042000201989 * Kaczorowski DJ, Billiar TR. Targeting CD47: NO limit on therapeutic potential (Circ. Research vol.100, issue 5, (pag. 602–3) 2007. doi= 10.1161/01.RES.0000261609.44977.25 * Mawby WJ, Holmes CH, Anstee DJ. Isolation and characterization of CD47 glycoprotein: a multispanning membrane protein which is the same as integrin-associated protein (IAP) and the ovarian tumour marker OA3. Biochem. Journal vol.304 (pag. 525–30) 1995 doi= * Cherif-Zahar B, Raynal V, Gane P. Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency Nat. Genet. vol.12(2) (pag. 168–73) 1996 . doi= 10.1038/ng0296-168 * Chung J, Gao AG, Frazier WA. Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3. Journal of Biological Chemistry (vol.272, issue 23, pag.14740–6, 1997). pmid= 9169439 . doi=10.1074/jbc.272.23.14740 * Jiang P, Lagenaur CF, Narayanan V. Integrin-associated protein is a ligand for the P84 neural adhesion molecule J. Biol. Chem. (vol.274, issue 2, pag. 559–62, 1999). pmid= 9872987 . doi=10.1074/jbc.274.2.559 * Chung J, Wang XQ, Lindberg FP, Frazier WA. Thrombospondin-1 acts via IAP/CD47 to synergize with collagen in alpha2beta1-mediated platelet activation . Blood (vol.94, issue 2, pag.642–8, 1999) pmid= 10397731 . doi= * Longhurst CM, White MM, Wilkinson DA, Jennings LK. A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX complex on the surface of human platelets is influenced by alphaIIbbeta3 conformational states. Eur. Journal Biochemistry (vol.263, issue 1, pag. 104–11, 1999) . pmid= 10429193 . doi=10.1046/j.1432-1327.1999.00467.x * Mateo V, Lagneaux L, Bron D. CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia National Medicine (vol.5, issue 11, pag.1277–84, 1999) . pmid= 10545994 . doi= 10.1038/15233 * Willingham SB, Volkmer JP, Gentles AJ. The CD47-signal regulatory protein alpha (SIRPα) interaction is a therapeutic target for human solid tumors Proceeding National Academy of Sciences USA (vol.109, issue 17, pag.6662-7, 2012) . pmid= 22451913 . doi= 10.1073/pnas.1121623109 . * Edris B, Weiskopf K, Volkmer AK. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma Proceedings Natl. Academy of Science USA (2012) Vol 109, Issue 17, (pages 6656-61) doi= 10.1073/pnas.1121629109. * Soto-Pantoja DR, Stein EV, Rogers NM. Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47 Expert Opinion Therapy Targets (vol.17, issue 1, pag.89-103, 2013) . pmid= 23101472 . doi= 10.1517/14728222.2013.733699 * Jiang H, Fu R, Wang H CD47 is expressed abnormally on hematopoietic cells in myelodysplastic syndrome Leukemia Research (vol.37, issue 8, pag.907–910, 2013 ) . pmid= 23642736 . doi= 10.1016/j.leukres.2013.04.008 * Zhang Y, Sime W, Juhas M, Sjölander A Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration European Journal of Cancer (vol.49, issue 15, pag.3320–34, June 2013) . pmid = 23810249 . doi = 10.1016/j.ejca.2013.06.005 * Starr JS, Jiang L, Li Z, Qiu Y, Menke DM, Tun HW CD47 and Osteopontin Expression in Diffuse Large B-cell Lymphoma With Nodal and Intravascular Involvement Clinical Lymphoma Myeloma Leukemya (vol.13, issue 5, pag. 597–601, June 2013) . pmid = 23810243 . doi = 10.1016/j.clml.2013.05.001 * Venkatraman L, Tucker-Kellogg L. The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells Liver Internist (vol.33, issue 9, pag.1386–97, May 2013) pmid = 23799952 . doi = 10.1111/liv.12231 . Collegamenti esterni * * http://www.pathologyoutlines.com/topic/cdmarkerscd47.html * Fonti * Category:Clusters of differentiation Category:Cancer research